Posted on 09/07/2021 1:04:45 PM PDT by NoLibZone
Abstract
A recent retrospective study has provided evidence that COVID-19 infection may be notably less common in those using supplemental melatonin. It is suggested that this phenomenon may reflect the fact that, via induction of silent information regulator 1 (Sirt1), melatonin can upregulate K63 polyubiquitination of the mitochondrial antiviral-signalling protein, thereby boosting virally mediated induction of type 1 interferons. Moreover, Sirt1 may enhance the antiviral efficacy of type 1 interferons by preventing hyperacetylation of high mobility group box 1 (HMGB1), enabling its retention in the nucleus, where it promotes transcription of interferon-inducible genes. This nuclear retention of HMGB1 may also be a mediator of the anti-inflammatory effect of melatonin therapy in COVID-19—complementing melatonin’s suppression of nuclear factor kappa B activity and upregulation of nuclear factor erythroid 2-related factor 2. If these speculations are correct, a nutraceutical regimen including vitamin D, zinc and melatonin supplementation may have general utility for the prevention and treatment of RNA virus infections, such as COVID-19 and influenza.
Keywords: coronary artery disease, acute coronary syndrome, coronary vessels Melatonin supplementation may reduce risk for COVID-19
A retrospective analysis of 791 intubated patients with COVID-19 has found that, after adjustment for pertinent demographics and comorbidities, those treated with melatonin had a markedly lower risk for mortality (HR: 0.131, 95% CI: 0.076 to 0.223)—suggestive of a profound anti-inflammatory benefit.1 Such an effect might be anticipated, in light of melatonin’s ability to upregulate expression of silent information regulator 1 (Sirt1)—a deacetylase that is known to suppress the activity of the proinflammatory nuclear factor kappa B (NF-kappaB) transcription factor—and also upregulate nuclear factor erythroid 2-related factor 2 (Nrf2), which promotes the transcription of a range of antioxidant proteins.2–4 Moreover, recent epidemiology suggests that melatonin usage may reduce the risk for contracting COVID-19. A recent retrospective study, examining data from 26 799 subjects in a COVID-19 registry and using propensity score matching to account for a range of covariates, found that current supplementation with melatonin was associated with a significant 28% reduction in risk for serologically detectible COVID-19 infection. Among Black Americans, this reduction in risk was a remarkable 52% (OR=0.48, 95% CI 0.31 to 0.75).5 The basis of this decrease in risk for COVID-19 is unclear, especially since Sirt1 activity, which melatonin promotes, is known to transcriptionally upregulate expression of ACE2—the cellular membrane receptor for COVID-19.6 7
Melatonin-induced Sirt1 may boost virally mediated mitochondrial antiviral-signalling (MAVS) activation
Here is a possible explanation. Melatonin, via its membrane receptors, induces nuclear translocation of the transcription factor retinoid-related orphan receptor alpha (RORα); RORα, in turn, promotes transcription of the gene encoding the clock transcription factor brain and muscle ARNT-like 1 (Bmal1). Bmal1 upregulates transcriptionally the expression of a number of proteins, including Sirt1 and Nrf2.2 8 9 The MAVS protein is a key mediator in the pathway of double-strand RNA sensing that leads to activation of interferon regulatory factor 3 (IRF3) and induction of type 1 interferons; its K63 polyubiquitination via TRIM31 triggered by upstream detectors of cytosolic double-stranded RNA, such as melanoma differentiation-associated protein 5 and RIG1, enable it to form multimers that promote activating phosphorylation of IRF3, which in turn induces the type 1 interferons.10–12 But the ubiquitinase ovarian tumour ubiquitinase 3 (OTUD3) opposes this activation by deubiquitinating MAVS.13 The activity of OTUD3 in this regard hinges on acetylation of its Lys129; Sirt1 can remove this acetyl group, turn off OTUD3 activity and thereby upregulate viral activation of MAVS and type 1 interferon induction.13 For reasons still unclear, RNA viral infection causes Sirt1 to associate with OTUD3, such that the latter is deacetylated and thereby inactivated, enabling the K63 polyubiquitination of MAVS and subsequent multimer formation.13 figure 1 attempts to clarify these relationships.
The net effect of Sirt1 on interferon-mediated antiviral immunity is however complicated by the fact that Sirt1 inhibits NF-kappaB’s transcriptional activity; NF-kappaB also functions downstream from MAVS to promote the induction of type 1 interferons.11 14 15 The cellular response to RNA viruses typically activates IRF3, NF-kappaB, ATF2 and c-Jun, all of which can bind to the promoter of the interferon-β gene and promote its transcription. However, there is evidence that activation of IRF3, in the absence of NF-kappaB, ATF2 or c-Jun activation, can drive transcription of the interferon-β gene.16 Notably, in HEK293T cells infected with Sendai virus, transfection with Sirt1 more than doubles the mRNA expression of interferon-β1, despite the potential inhibitory impact of Sirt1 on NF-kappaB activity.13 Analogously, resveratrol, a Sirt1 activator, doubles interferon-β mRNA induction in Huh7 cells infected with dengue virus.17
In light of the fact that melatonin enhances Sirt1 expression via activation of Bmal1, it is pertinent that knockout of Bmal1 in mice impairs their ability to control pulmonary infections with the Sendai and influenza RNA viruses.18
Sirt1 may also amplify response to interferons by preventing nuclear export of high mobility group box 1 (HMGB1)
Sirt1 activity may also boost the antiviral response triggered by type 1 interferons. In response to inflammatory signals or certain viral infections, the damage-associated molecular pattern protein HMGB1 is hyperacetylated, causing its export from the nucleus and enabling its release from the cell.19 The p300/CBP-associated factor acetylase complex can mediate this acetylation, as has been demonstrated in dengue virus-infected cells.20 By reversing such acetylation, Sirt1 tends to keep this protein confined to the nucleus, where it has been shown to boost the transcription of type 1 interferon-stimulated antiviral genes.17 21 22 In this regard, HMGB1 has been shown to associate with the promoter region of the interferon-stimulated gene MxA.17 Indeed, the acetylation of HMGB1, triggered by viral infection, may represent a viral stratagem for suppressing expression of these antiviral genes. Hence, measures which enhance Sirt1 activity may both potentiate RNA virus-mediated induction of interferon-β and also render cells more sensitive to the antiviral activity of this cytokine. Figure 1 summarises these pathways.
I take 3 - 5 mg of melatonin occasionally to help me sleep. Do not recall any nightmares, but not sure about bp. I’ll monitor mornings with and without melatonin.
Actually, I thought recent rise in bp was because I wasn’t going to the gym. That mile a day on the treadmill is very good for keeping bp down. Exercise, calcium, magnesium and lots of water—supposedly the magic formula.
Might as well add it to the bucket of supplements I’m taking already.
just took bp. Off the charts for. me. Bye-bye going to gym with my water bottle.
I have read of famotidine being used.
Thank you!
If you want to care of your health, look at removing unnecessary iron from your body. I donate blood every two years. There are many reasons. Groups at higher risk for wuhan coronavirus have more stored iron.
You are not supposed to split the extended release versions. If the tablet is scored, you should be able to split it. Check the bottle for warnings against splitting.
I used to regularly split 3 mg tablets so I could take about 5mg.
Black privelege again. They have more melatonin in their skin.
Take it 60-90 minutes before you intend to go to sleep.
LOL. Yup...she always said that but we young’uns never listened....(thanks for the chuckle!)
I too sometimes take 5mg at night...and it scarily makes me almost comatose until the next morning, and then I spend a full day groggy and non-functional. The amounts suggested here (36-72mg) have to be for very severe cases of Covid.
Bookmark
“36 to 72 mg”
Seems like a lot, since I occasionally take 5 mg if I have trouble falling asleep.
Sounds awful. I'm groggy and non-functional if I DON'T take it, since I don't get enough sleep.
Melatonin also improves my dreams.
Sorry, Vitamin D is too cheap to solve a national health crisis.
Can’t use that.
Quick! Buy melatonin before its removed from the health food supplement stores.
dose is for hospital setting to stop or prevent cytokine storm, for intubated serious patients.
For nightly use, I’d do about 1/10th what you take
Sirt1 may enhance the antiviral efficacy of type 1 interferons by preventing hyperacetylation of high mobility group box 1 (HMGB1), enabling its retention in the nucleus, where it promotes transcription of interferon-inducible genes. This nuclear retention of HMGB1 may also be a mediator of the anti-inflammatory effect of melatonin therapy in COVID-19—complementing melatonin’s suppression of nuclear factor kappa B activity and upregulation of nuclear factor erythroid 2-related factor 2. If these speculations are correct, a nutraceutical regimen including vitamin D, zinc and melatonin supplementation may have general utility for the prevention and treatment of RNA virus infections, such as COVID-19 and influenza.
************************************************************
Exactly what I was thinking...
Bookmark
This is crazy. Vitamin C, D3, Zinc, Quercetin and Melotonin are ALL supplements I take, and have taken, for years.
I’m also 53 (just turned, today, as of 10:30 am Eastern Standard time!), I walk 5 miles a day, lift weights three times a week and love potato chips and salads.
While I’m not exactly thin (I’m a stocky little German American woman who can bench press my weight with a spotter and after a cup of coffee) my friends who are consantly demanding everyone get vaxxed for their ‘health’ also weigh closer to 300 and think a short trip to the kitchen from the couch is enough steps for the day...
For the record, I got the J&J one shot and spent 4 days with a high fever. Yes, I’m a sheep who got bullied into it because I’m not as ballsy as I’d like to think I am sometimes. Besides, my daughter, who is 18, decided to get the shot, so I figured, I’m taking what she took. She’s my baby, if she goes, I go.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.